Project 1 focuses on the linkage of nuclear architecture with gene regulation. Nuclear morphology is[unreadable] dramatically altered during hematopoietic differentiation and is diagnostic for oncogenic transformation[unreadable] and tumor progression. The hypothesis is that cooperative interactions between AML (RUNX) proteins[unreadable] and other gene regulatory factors at distinct subnuclear foci support myeloid-specific transcriptional[unreadable] control. One of the recent key findings of this program is that abrogation of AML1 subnuclear targeting[unreadable] causes a myeloid cell maturation arrest. Furthermore, a subnuclear targeting defect in the t(8;21)[unreadable] AML1/ETO fusion protein that is directly linked to the etiology of Acute Myelogenous Leukemia was[unreadable] established. This project therefore examines the (i) molecular mechanisms, (ii) gene regulatory[unreadable] pathways, (iii) physiological processes, and (iv) mitotic functions that are coupled to the subnuclear[unreadable] targeting dependent activity of AML1. We will characterize the molecular basis of subnuclear targeting[unreadable] during myeloid differentiation and its deregulation during leukemogenesis (Specific Aim 1)[unreadable] (collaboration with Projects 2 and 4). We will identify AML1 mediated regulatory pathways that depend[unreadable] on fidelity of intranuclear trafficking in myeloid cells (Specific Aim 2) (collaboration with Project 2). To[unreadable] establish the physiological relevance of our findings, we will examine the consequences of abrogating[unreadable] subnuclear targeting on biological control and cancer in murine animal models in vivo (Specific Aim 3).[unreadable] We will characterize AML-dependent mitotic control of gene expression and deregulation in cancer[unreadable] cells (Specific Aim 4) (collaboration with Projects 2, 3 and 4). These studies will provide a mechanistic[unreadable] understanding at multiple biochemical, cellular and physiological levels of signal integration at AML[unreadable] related subnuclear microenvironments that dynamically assemble to support AML responsive gene[unreadable] regulatory programs that are altered during the onset and. progression of Acute Myelogenous[unreadable] Leukemia.[unreadable] Lay Summary: The structure and shape of the cell nucleus, as well as the intranuclear organization[unreadable] and assembly of the regulatory machinery for gene expression, is dramatically modified during the[unreadable] onset and progression of leukemias. The goal of our project is to characterize how regulatory proteins[unreadable] function together at nuclear microenvironments to control gene expression and how this process is[unreadable] disrupted in leukemia. Our findings will provide a platform for novel approaches to cancer diagnosis[unreadable] and therapies.[unreadable]